Glutathione (L-γ-glutamyl-l-cysteinyl-glycine, GSH), a sulfhydryl-containing tripeptide produced by most mammalian cells, is an efficient scavenger of toxic oxidants, including hydrogen peroxide, an oxidant that plays a major role in the oxidant burden placed on the epithelial surface of the lower respiratory tract in chronic inflammatory states. GSH is present in the epithelial lining fluid of the normal lower respiratory tract, where it is thought to play a major role in providing antioxidant protection to the epithelial cells. In this regard, we hypothesized that the lower respiratory tract of patients with IPF may be chronically depleted of this antioxidant, thus leading to an increased susceptibility of lung epithelial cells to oxidant injury. To evaluate this concept, the concentration of glutathione was determined in the epithelial lining fluid of the lower respiratory tract of 15 patients with IPF and compared to that of 19 normal subjects. Strikingly, whereas ELF glutathione concentrations were high in normal subjects (429 ± 34 µM), a fourfold decrease was found in patients with IPF (97 ± 18 µM, p < 0.001). In the context of the known oxidant burden present in the lower respiratory tract of patients with IPF, these observations of a “GSH deficiency” in IPF ELF suggest that there is a marked oxidant-antioxidant imbalance at the alveolar surface of these persons, thus increasing the susceptibility to the severe epithelial cell damage characteristic of this disease.